Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

摘要: Protocadherins constitute the largest subgroup in cadherin superfamily of cell adhesion molecules. Their major functions are poorly understood, although some implicated nervous system development. As tumor-specific promoter methylation is a marker for tumor suppressor genes (TSG), we searched epigenetically inactivated TSGs using methylation-subtraction combined with pharmacologic demethylation, and identified PCDH10 CpG island as methylated sequence nasopharyngeal carcinoma (NPC). broadly expressed all normal adult fetal tissues including epithelia, though at different levels. It resides 4q28.3--a region hemizygous deletion detected by array-CGH NPC lines; however, itself not located within deletion. In contrast, its transcriptional silencing were frequently multiple lines biallelic way, 12/12 nasopharyngeal, 13/16 esophageal, 3/4 breast, 5/5 colorectal, cervical, 2/5 lung 2/8 hepatocellular lines, but any immortalized epithelial line. Aberrant was further primary carcinomas (82% NPC, 42-51% other carcinomas), tissues. The could be reversed demethylation 5-aza-2'-deoxycytidine or genetic double knockout DNMT1 DNMT3B, indicating direct epigenetic mechanism. Ectopic expression strongly suppressed growth, migration, invasion colony formation. Although disruptions several classical cadherins have been well documented tumors, this first report that widely protocadherin can also function TSG carcinomas.